Efficacy of front‐line ibrutinib versus fludarabine, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia: A retrospective multicenter “<scp>Real‐World</scp>” study
Authors: Shai Levi, Yotam Bronstein, Neta Goldschmidt, Fortunato Morabito, Tomer Ziv‐Baran, Giovanni Del Poeta, Osnat Bairey, Maria Ilaria Del Principe, Riva Fineman, Francesca Romana Mauro, Odit Gutwein, Gianluigi Reda, Rosa Ruchlemer, Paolo Sportoletti, Luca Laurenti, Lev Shvidel, Marta Coscia, Tamar Tadmor, Marzia Varettoni, Ariel Aviv, Roberta Murru, Andrei Braester, Annalisa Chiarenza, Andrea Visentin, Daniela Pietrasanta, Giacomo Loseto, Antonella Zucchetto, Riccardo Bomben, Jacopo Olivieri, Antonio Neri, Davide Rossi, Gianluca Gaidano, Livio Trentin, Robin Foà, Antonio Cuneo, Chava Perry, Valter Gattei, Massimo Gentile, Yair Herishanu
Journal: American Journal of Hematology (2022)

In recent years, there has been a dramatic change in the treatment landscape of chronic lymphocytic leukemia (CLL). The chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab (FCR) has been shown to prolong progression-free survival (PFS) and overall survival (OS) compared to FC alone in previously untreated CLL patients.1 Consequently, until recently FCR has become the treatment of choice in young fit patients with CLL. Ibrutinib, a first-in-class covalent inhibitor of Bruton's tyrosine kinase, improved PFS and OS compared to chlorambucil2 and prolonged PFS compared to bendamustine plus rituximab, as frontline treatment in older (≥65 years) patients with CLL.3 In phase the III ECOG-E1912 trial, ibrutinib plus rituximab (IR) has been shown to prolong PFS and OS compared to FCR in treatment-naïve (TN) CLL patients aged <70 years.4, 5 At 3 years, a subgroup analysis showed a PFS superiority with IR compared to FCR only in patients with unmutated (U) immunoglobulin heavy chain variable region gene (IGHV).4 However, with a longer follow-up of 5 years, an improvement in PFS with IR was apparent in the mutated (M) IGHV subgroup as well.5 A better PFS in frontline treatment with IR over FCR had also been shown in the phase III NCRI FLAIR trial, yet with no OS difference, and currently, the improved PFS with IR is observed only in the U-IGHV group.6 In this retrospective, bi-national, multicenter "real-world" study, we compared the PFS and OS between ibrutinib and FCR in previously untreated CLL patients. Patients with documented del(17p13.1) or TP53 mutations were excluded. Demographics and clinical data were retrieved from the Israeli CLL Study Group database (1996–2020) and the Italian multicenter "Campus CLL" network (2015–2020). The study was approved by the institutional Helsinki ethics committees of the participating centers. In order to fit both treatment groups, the maximum follow-up was censored at 48 months. For controlling differences in patients' characteristics, we use the inverse probability of treatment weighting method. For more details on the statistical analysis, see Supplementary Appendix. A total of 235 patients treated in first-line either with FCR (n = 136, 57.9%) or ibrutinib (n = 99, 42.1%), were included (baseline demographic and disease characteristics are listed in Table S1). FCR treated patients were younger compared to patients treated with ibrutinib (mean = 57.6 years [±7.5] versus 71.6 years [±8.7]; p < .001). In the entire cohort, most patients were males (n = 160, 68.1%), had U-IGHV (n = 115, 70.6%) and Binet stage B/C (n = 191, 83.8%). The most frequent chromosomal aberration was del(11q) (n = 45, 23.1%) followed by trisomy 12 (n = 34, 17.4%) and del(13q) (n = 43, 22.1%). The median time from CLL diagnosis to first treatment was 29.4 months (IQR, 11.9–56.2) and was not significantly different between the ibrutinib (median = 24.9 months, IQR 10.3–46.6) and FCR cohorts (median = 33.5 months, IQR 13.8–59.3; p = .164). The median follow-up for the entire cohort was 48.0 months; 37.2 months for ibrutinib and 48.0 months for the FCR cohort. During the study follow-up, a total of 66 patients (28.1%) progressed (ibrutinib: n = 10, 10.1%; FCR: n = 56, 41.2%). The PFS was shorter in patients treated with FCR than with ibrutinib; a 4-year PFS rate of 54.8% versus 87.7%, respectively (hazard ratio (HR) = 3.6, 95% CI [1.84–7.06]; p < .001) (Figure 1A, Supplementary Table S3). The PFS difference between these treatments protocols was also noted in 3-year analysis (65.0% vs 89.7%, HR = 3.3, 95% CI [1.63–6.83], p < .001). By subgroup analysis, the PFS was significantly longer among patients with age at treatment initiation <65 years compared with age at initiation ≥65 years (HR = 0.6, 95% CI [0.33–0.96], p = .036) and among patients without FISH abnormalities (HR = 0.5, 95% CI [0.25–0.95], p = .036) (Table S2) Four-year PFS was shorter among U-IGHV patients treated with FCR compared to patients treated with ibrutinib (44.9% vs. 89.5%; HR = 5.8, 95% CI [2.35–14.46]; p < .001) (Figure 1B) but it did not reach a statistically significant difference in the M-IGHV group (4-year PFS: 67.0% vs. 83.0%, respectively; HR = 1.5, 95% CI [0.41–5.24]; p = .551) (Figure 1C). As expected, 4-year PFS among patients treated with FCR was trendy shorter in the U-IGHV compared with M-IGHV subgroup, but without statistical significance (44.9% vs. 67.0%, respectively; HR = 2.2, 95% CI: 0.89–5.49; p = .087), while there was no difference in PFS among patients treated with ibrutinib stratified by IGHV mutational status (4-year PFS: 83.0% vs. 89.5% in M-IGHV and U-IGHV respectively; HR = 0.5, 95% CI [0.15–1.88]; p = .326). In a multivariate analysis, FCR was the only independent variable associated with reduced PFS (HR = 4.3, 95% CI [1.92–9.60], p = <0.001) (Table S3). Given the imbalance in age between the ibrutinib and FCR groups, we confirmed by inverse probability of treatment weighting the PFS inferiority with FCR compared to ibrutinib (HR = 4.5, 95% CI [2.1–10.0], p < .001). A total of 22 patients (9.4%) died during the 48-months study period (Table S5); 19 (14.0%) in the FCR cohort and 3 (3.0%) in the ibrutinib cohort. OS was shorter in patients treated with FCR compared with ibrutinib, with a 4-year OS rate of 84.7% vs. 96.8%, respectively (HR = 3.5, 95% CI [1.04–11.97]; p = .043) (Figure 1D, Table S4). A similar analysis at 3 years showed only a trend toward statistical significance between FCR and ibrutinib (87.4% vs. 96.8%, respectively; HR = 3.1, 95% CI: 0.90–10.63; p = .073). By subgroup analysis, none of the variables were found to prolong the OS among the study's cohort, and multivariate analysis was not performed. Using the inverse probability of treatment weighting, we confirmed an OS inferiority with FCR compared to ibrutinib (HR = 5.3, 95% CI [1.5–18.3], p = .008). For additional sub-groups statistical analysis, see Supplementary Appendix. In this multicenter retrospective, real-world study, we show that frontline treatment with ibrutinib improved both PFS and OS over FCR in patients with CLL during 48 months of follow-up. To compare our findings with previous studies, we analyzed our findings also for 3-year of follow-up. Our results seem to be similar to the results reported in the phase III ECOG-E1912 and FLAIR trials, which showed a better PFS with frontline IR compared to FCR,4-6 whereas OS advantage with IR was observed only in the ECOG-E1912 trial.4, 5 In our study, the 3-year PFS with ibrutinib (89.7%) is comparable to the PFS reported with IR in the ECOG-E1912 trial (89.4%).4 It has been previously shown that the addition of rituximab to ibrutinib does not improve PFS compared to ibrutinib alone in patients with CLL.3, 7 On the other hand, the 3-year PFS rate in patients treated with FCR (65.0%) in our cohort, seems to be lower than reported in the ECOG-E1912 trial (72.9%).4 It is important to note that in a real-world setting, more intensive treatment regimens like FCR were often reported to achieve inferior PFS probably due to a lack of patient selection (thus including patients with multiple comorbidities and less fit patients) and more frequent dose reductions.8 Furthermore, the 3-year OS rates in our patients treated with ibrutinib (96.8%) and FCR (87.4%) are also comparable to those reported with IR and FCR (98.8% and 91.5%, respectively) in the ECOG-E1912 trial.4 This favorable OS in our FCR-treated patients may have been due to the introduction of targeted therapies into second-line treatment onwards. In our study, treatment with ibrutinib improved PFS in the U-IGHV but not in the M-IGHV subgroup. No similar differences were observed in the OS analysis. A similar favorable PFS with ibrutinib has been reported in U-IGHV patients both in the ECOG-E1912 and FALIR trials.4-6 Lack of PFS advantage with ibrutinib in M-IGHV patients had been observed in the first 3 years of follow-up in both the ECOG-E1912 trial as well as in the NCRI FLAIR study,4, 6 yet, with a longer follow-up of 5 years, treatment with IR emerged to improve PFS also in the M-IGHV subgroup, in the ECOG-E1912 trial.5 Thus, it is indeed possible that with longer follow-up, an improvement in PFS in the M-IGHV subgroup can also be expected in our cohort. Our study has several limitations; first, our data were retrospectively collected from multiple centers, which may potentially cause lack of uniformity in the data analysis. In addition, there was an age imbalance between the two treatment cohorts, with a younger age among FCR-treated patients versus ibrutinib. However, by inverse probability of treatment weighting, we confirmed that PFS is superior with ibrutinib over FCR. In addition, the older age in the ibrutinib cohort was in fact expected to adversely affect outcomes and therefore reinforce our results. In conclusion, in a real-world setting frontline treatment with ibrutinib improved PFS and OS compared to FCR in patients with CLL in 48 months of follow-up. The improvement in PFS was preferentially observed in patients with unmutated IGHV. Overall, these real-world results are comparable to the results reported in clinical trials and therefore further support ibrutinib as a preferred option over FCR in first-line treatment in CLL. SL and YB wrote the manuscript and analyzed the data. TZB analyzed the data. YH initiated and supervised the study, and wrote the manuscript. All co-authors except TZB collected the clinical data. The present study is supported in part by: Progetto Ricerca Finalizzata PE-2016-02362756, and RF-2018-12 365 790, Italian Ministry of Health, Rome, Italy; Associazione Italiana Ricerca Cancro (AIRC), Investigator Grant IG-21687; Associazione Italiana contro le Leucemie, linfomi e mielomi (AIL), Venezia Section, Pramaggiore/Veneto Orientale Group, Italy; Fundaciò La Maratò de TV3 (Spain); Linfo-check - Bando ricerca - contributo art. 15, comma 2, lett (b) LR 17/2014; "5 × 1000 Intramural Program", Centro di Riferimento Oncologico, Aviano, Italy. Yair Herishanu received honoraria from AstraZeneca, Janssen, AbbeVie, Roche and Medison that unrelated to this study. The remaining authors declare no potential conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. The data that support the findings of this study are available from the corresponding author upon reasonable request. Appendix S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.